Neoadjuvant ipilimumab, relatlimab, and nivolumab combinations for resectable cutaneous and mucosal melanoma

A Phase II, Multicentre, Parallel Group, Open Label, Randomised Clinical Trial of Neoadjuvant Nivolumab and Ipilimumab Combined With Relatlimab for Patients With Resectable Advanced Melanoma Identified as Poor Responders to Immunotherapy

This phase 2 trial will test several immunotherapy combinations given before surgery to try to reduce recurrence in adults with resectable stage 3 cutaneous melanoma or resectable mucosal melanoma, including patients predicted or known to respond poorly to standard anti‑PD‑1 therapy.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 494 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Melanoma Institute Australia (other)
• Drugs / interventions: relatlimab, ipilimumab, nivolumab, prednisone, immunotherapy, pembrolizumab
• Locations: 1 site (Wollstonecraft, New South Wales)
• Trial ID: NCT06999980 on ClinicalTrials.gov

What this trial studies

This randomized phase 2 trial enrolls three cohorts: resectable stage 3 cutaneous melanoma patients stratified by a multi‑omic predictive biomarker into predicted poor- or high-responders, patients with resectable recurrence after prior anti‑PD‑1 therapy, and patients with any-stage resectable mucosal melanoma. Participants receive one of six neoadjuvant immunotherapy regimens (combinations of ipilimumab, nivolumab, relatlimab, or pembrolizumab) prior to definitive surgery. Tumor core biopsies and multi‑omic testing guide cohort assignment and allow correlation of biomarker status with pathologic and clinical responses. The primary goal is to identify regimens that improve pathologic response and reduce recurrence in groups that typically respond poorly to standard anti‑PD‑1 therapy.

Who should consider this trial

Good fit: Adults (≥18) with fully resectable disease, ECOG 0–1, able to undergo a new core tumor biopsy and definitive surgery, including stage 3 cutaneous patients eligible for biomarker stratification, patients with recurrence after anti‑PD‑1, and patients with resectable mucosal melanoma.

Not a fit: Patients with unresectable disease, poor performance status, significant organ dysfunction, inability to undergo biopsy or planned surgery, or who do not meet inclusion criteria are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, these neoadjuvant combinations could lower recurrence rates and improve long‑term outcomes for patients who currently respond poorly to standard anti‑PD‑1 therapy.

How similar studies have performed: Previous neoadjuvant trials of ipilimumab plus nivolumab and recent data on relatlimab plus nivolumab have shown encouraging response signals, but applying multi‑omic biomarker selection to test these six combination regimens in poor‑responder cohorts is relatively novel.

Eligibility criteria

COMMON Inclusion Criteria Applicable to all 3 cohorts

Inclusion Criteria:

* 1\. Written informed consent
* 2\. Male or female patients who are at least 18 years of age on the day of signing informed consent.
* 3\. Clinically detectable disease, and/or RECIST version 1.1 defined disease, and/or disease confirmed on PET imaging.
* 4\. Fully resectable disease defined as having no significant vascular, central nervous system or bony involvement. Only cases where a complete surgical resection leading to tumour free margins and which is safely achieved is considered "resectable".
* 5\. Concurrent primary disease and lymph node metastases acceptable provided completely resectable.
* 6\. Up to 3 in-transit metastases are permitted as long as these are fully resectable.
* 7\. Tumour that is amenable to a newly obtained core biopsy for performance of the multi-omic predictive biomarker model
* 8\. ECOG performance status of 0 to 1.
* 9\. Adequate haematological, hepatic, renal and endocrine function
* 10\. An anticipated life expectancy of \>12 months.
* 11\. Women of child bearing potential (WOCBP) must agree to avoid pregnancy or breast feeding for the duration of study treatment.

Inclusion Criteria - Cohort 1 only

* a. Histologically confirmed diagnosis of cutaneous melanoma or unknown primary melanoma
* b. AJCC 8th Ed Stage IIIB, IIIC, IIID cutaneous melanoma
* c. No prior systemic treatment for cutaneous melanoma
* d. Completion of the multi-omic predictive biomarker model within 14 days (7-10 business days) of planned randomisation.

Inclusion Criteria - Cohort 2 only

* a. Histologically confirmed diagnosis of cutaneous melanoma or unknown primary melanoma
* b. AJCC 8th Ed Stage IIIB, IIIC, IIID cutaneous melanoma
* c. Disease progression on neoadjuvant anti-PD-1 monotherapy, where progressed disease is completely resectable or, disease recurrence on adjuvant anti-PD-1 monotherapy, where recurrent disease is completely resectable
* d. No prior treatment with CTLA-4 or LAG-3 inhibitors.

Inclusion Criteria - Cohort 3 only

* a. Histologically confirmed diagnosis of mucosal melanoma
* b. Any stage of disease provided it is fully resectable
* c. No prior systemic treatment for mucosal melanoma

COMMON Exclusion Criteria Applicable to all 3 cohorts

* 1\. Uveal melanoma
* 2\. Any contraindication to the administration of relatlimab, ipilimumab or nivolumab
* 3\. No prior systemic therapy, including treatment with prior anti-PD1/L1, anti-CTLA-4 or anti-LAG-3 therapy (cohorts 1 and 3), except for cohort 2 which will have received anti-PD1 monotherapy only.
* 4\. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days of randomisation. The following are permitted:

  1. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)
  2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose
  3. Non-absorbed intra-articular steroid injections.
* 5\. An active autoimmune disease that has required systemic treatment in the past 12 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). The following are permitted:

  1. Vitiligo
  2. Type I diabetes mellitus
  3. Residual autoimmune hypothyroidism on stable hormone replacement
  4. Resolved childhood asthma or atopy
  5. Psoriasis not requiring systemic treatment
  6. Autoimmune conditions which are not expected to recur in the absence of an external trigger.
* 6\. A known additional malignancy that is progressing or has required active treatment within the past 3 years. The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:

  1. Basal cell carcinoma of the skin
  2. Squamous cell carcinoma of the skin
  3. Carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy)
  4. Prostatic intraepithelial neoplasia
  5. In situ melanoma
  6. Atypical melanocytic hyperplasia
  7. Multiple primary melanomas
  8. Other malignancies for which the patient has been disease free for 1 year.
* 7\. A known CNS metastases and/or carcinomatous meningitis
* 8\. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease.
* 9\. Has an active infection requiring systemic therapy.
* 10\. Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.
* 11\. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
* 12\. Has a known history of active TB (Bacillus Tuberculosis).
* 13\. Uncontrolled or significant cardiovascular disease including, but not limited to any of the following:

  1. Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months prior to consent
  2. Uncontrolled angina within the 3 months prior to consent
  3. Any history of clinically significant arrhythmias (such as poorly controlled atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
  4. QTc prolongation \> 480 ms
  5. History of other clinically significant cardiovascular disease (i.e. cardiomyopathy, congestive heart failure with New York Heart Association functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled venous thrombosis, etc)
  6. Cardiovascular disease-related requirement for daily supplemental oxygen
  7. History of 2 or more M.I.s OR 2 or more coronary revascularisation procedures (regardless of the number of stent placements during each procedure)
  8. Patients with history of myocarditis, regardless of aetiology.
* 14\. Patients with a \>1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is \<1 g/24 hours.
* 15\. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
* 16\. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* 17\. Pregnant or breast feeding females
* 18\. Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule

Where this trial is running

Wollstonecraft, New South Wales

• Melanoma Institute Australia — Wollstonecraft, New South Wales, Australia (RECRUITING)

Study contacts

• Study coordinator: Monica Osorio

Conditions: Cutaneous Melanoma, Mucosal Melanoma, Neoadjuvant, Immunotherapy, Randomised trial, Low Responder